The present invention relates to methods and compositions for the treatment of cancer.
One drug that has proven effective in the treatment of certain tumors is cisplatin (cis-dichlorodiamine-platinum(II)). However, cisplatin has certain disadvantages. For example, its use in some circumstances is limited by its toxicity to the patient, especially its nephrotoxicity. As another example, tumors sometimes develop resistance to cisplatin.
In an effort to overcome the disadvantages of cisplatin, researchers have synthesized and tested various other platinum complexes as potential antitumor agents. One such compound is dichloro(1,2-diaminocyclohexane) platinum(II) (referred to in the remainder of this patent as xe2x80x9cDACHxe2x80x94Ptxe2x80x94Cl2xe2x80x9d). However, this compound has very low solubility in water, making it impractical for formulation and administration in aqueous solution. Further, although various platinum complexes have been formulated in liposomes in the past, a liposomal formulation of DACHxe2x80x94Ptxe2x80x94Cl2 has not been developed because that complex is insoluble in most organic solvents. Although it has good solubility in dimethylformamide, that solvent has a very high boiling point, therefore making it impossible or impractical to prepare a liposomal formulation of DACHxe2x80x94Ptxe2x80x94Cl2 using standard evaporation methods.
Other platinum-based antitumor drugs, such as cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP) have been prepared and tested as antitumor agents. However, a need still exists for improved antitumor drug formulations that have good antitumor activity, low toxicity to non-cancerous cells in a patient, and desirable storage characteristics.
The present invention relates to a liposomal antitumor composition and to methods of using the composition to inhibit tumor growth in mammals. The invention also concerns methods of preparing the antitumor composition.
The present invention can take advantage of intraliposomal conversion of a platinum complex having the formula 
into a complex having the formula
R1xe2x80x94Ptxe2x80x94X2xe2x80x83xe2x80x83(II) 
where X is halogen. This makes it possible to prepare liposomal formulations of the complex (II), which had not been practical previously due to its low solubility in water and most organic solvents.
In the above complexes, R1 is diaminocycloalkyl, preferably a 1,2-diaminocycloalkyl group having from about 3 to about 6 carbon atoms, most preferably 1,2-diaminocyclohexane. R2 and R3 each have the formula 
where R4, R5, and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, preferably alkyl having from 1 to about 6 carbon atoms, most preferably alkyl having from 1 to about 3 carbon atoms. R2 and R3 can be the same but do not have to be the same. Likewise, R4, R5, and R6 can be the same but do not have to be the same. X is most preferably chlorine.
One aspect of the present invention is a liposomal antitumor composition that comprises the complex (II) entrapped in a liposome. In a particular embodiment of the invention, the liposome comprises an acidic phospholipid, for example dimyristoyl phosphatidyl glycerol. Without being bound by theory, it is believed that the presence of the acidic phospholipid in the liposome enhances or accelerates the conversion of the complex (I) to the complex (II).
Another aspect of the present invention is a method of inhibiting tumor growth. The method comprises administering to a mammal a composition that comprises the complex (II) entrapped in a liposome, with the platinum complex being present in an amount effective to inhibit tumor growth.
Another aspect of the present invention is a method of preparing the antitumor composition. This method comprises the step of adjusting the pH of a composition that comprises the platinum complex (I) entrapped in a liposome, whereby the pH is made somewhat acidic, preferably between about 2 and about 6.5, resulting in the conversion of the complex (I) into the complex (II). The resulting composition can then be administered to a patient.
In one particular embodiment of this method, the complex (I) is converted to the complex (II) within the liposome. This allows a liposomal formulation of the complex (I) to be manufactured and stored, and then shortly before administration to a patient, the liposomal formulation of complex (I) can be converted to a liposomal formulation of complex (II) in situ by simply adding an acidic solution to the formulation. Optionally, after a predetermined time has passed since the addition of the acidic solution, the pH can be readjusted, preferably to at least about 7, in order to stop the conversion of complex (I) to (II).
A broader aspect of the invention concerns a method of delivering a biologically active chemical moiety internally to a mammal. The biologically active moiety can be, for example, an antitumor agent. The method comprises (a) providing an aqueous formulation of a prodrug of the biologically active moiety, the prodrug being entrapped in a liposome, and the prodrug further being capable of forming the biologically active moiety upon exposure to a solution having an acidic pH; (b) reducing the pH to an acidic level, thereby converting the prodrug to the biologically active compound; and (c) administering the aqueous formulation to a mammal. Administration of the liposomal formulation to the mammal can suitably be done after the conversion of the prodrug, but it might also be done before conversion, such that the conversion would then occur in vivo, for example due to acidic components (e.g., acidic phospholipids) of the liposome.
The present invention has a number of advantages over prior art platinum antitumor formulations and methods, including better antitumor activity, greater potency, and reduced toxicity to non-cancerous cells of the patient. Further, the compositions of the present invention permit the formulation in liposomes and the delivery of platinum complexes that could not be so formulated in the past.